Zugl.: Hagen, Fernuniv., Diss., 2007

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There is two different ways to react to a disease like Mild cognitive impairment and Alzheimer’s disease, pathological and clinical. What if there was a way to delay the clinical expression of a disease through pathology? The cognitive reserve has been proven to show a more rapid decline in the individuals that had higher reserve. The purpose of this study was to see if the cognitive reserve actually had an impact on the outcome of Dementia and Alzheimer’s disease. A total of 53 patients with varying degrees of disease pathology and clinical symptoms participated in the study. The results demonstrated that the cognitive reserve makes an impact on the clinical expression, the individuals with high cognitive reserve have a delayed clinical expression comparatively with those with low reserve. Studies of the cognitive reserve may point the way to successful interventions that can help maintain successful aging and slow the onset of dementia.

Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

Universiẗat, Diss., 2001--Bonn.

Proefschrift Maastricht. / Met lit. opg. - Met een samenvatting in het Engels.

Les dinoflagellés epi-benthiques Gambierdiscus et Fukuyoa produisent les ciguatoxines (CTXs) et les maïtotoxines (MTXs), qui sont parmi les toxines marines les plus puissantes connues. Les CTXs sont bioaccumulées et bio-transformées le long de la chaîne alimentaire marine et provoquent la ciguatéra, l'intoxication alimentaire non bactérienne la plus commune au monde. Récemment, la ciguatéra a été rapporté dans des zones non endémiques, notamment les îles Canaries, et un grand nombre d'espèces a été découvert au sein de ces genres. Peu de données sont disponibles sur la toxicité relative entre les différentes espèces et sur les congénères de toxines produits par ces dinoflagellés, en particulier par des souches en dehors de l'océan Pacifique. Plusieurs souches de Gambierdiscus et Fukuyoa ont été examinées pour leur cigua- et maïto-toxicité via les tests neuro-2a et hémolytique, respectivement. G. excentricus a montré une forte toxicité et deux souches des îles Canaries ont été sélectionnées pour la purification des toxines via une approche de fractionnement bioguidé. L'analyse non-ciblée de spectrométrie de masse (SM) à haute résolution a permis la découverte d'un nouveau congénère de MTX, la maïtotoxine-4 (MTX4). La SM à basse résolution de plusieurs souches de Gambierdiscus et Fukuyoa n’a révélé la présence de MTX4 que dans G. excentricus, y compris des souches provenant des îles Canaries, du Brésil et du Golfe du Mexique. La MTX4 pourrait donc servir de biomarqueur pour l’espèce hautement toxique G. excentricus. Les travaux futurs porteront sur l'isolement et l'élucidation de la structure de la MTX4 et l'identification des congénères de CTX produits par G. excentricus. / The epi-benthic dinoflagellates Gambierdiscus and Fukuyoa produce ciguatoxins (CTXs) and maitotoxins (MTXs), which are among the most potent marine toxins known. CTXs are bio-accumulated and bio-transformed along the marine food chain and cause Ciguatera Fish Poisoning (CFP), the most common non-bacterial foodborne intoxication worldwide. Recently, CFP has been reported from areas previously not considered endemic, namely the Canary Islands, and an increasing number of species has been discovered in these genera. Little is known about the relative toxicity between different species and the toxin congeners produced by these dinoflagellates, especially by strains outside the Pacific Ocean. Several strains of Gambierdiscus and Fukuyoa were screened for their cigua- and maito-toxicity using neuro-2a and hemolytic assays, respectively. G. excentricus showed particularly high toxicity and two strains from Canary Islands were selected for toxin purification using a bioguided fractionation approach. Non-targeted high resolution mass spectrometry (MS) analysis permitted the discovery of a novel MTX congener, maitotoxin-4 (MTX4). Targeted low resolution MS analysis of more than 40 strains of Gambierdiscus and Fukuyoa revealed the presence of MTX4 in G. excentricus only, including strains from the Canaries, the South Western Atlantic (Brazil) and the North Western Atlantic (Gulf of Mexico). As MTX4 was not detected in any other species examined, MTX4 may serve as a biomarker for the highly toxic G. excentricus. Future work will include isolation and structural elucidation of MTX4 and identification of CTX congeners produced by G. excentricus.

BACKGROUND: Gliomas are the most common primary brain malignancy, with more than 16,000 patients diagnosed every year (Ostrom, et al., 2015). Outcomes vary widely depending on tumor grade and treatment, and have been steadily improving with the advent of new therapeutics. Glioma patients frequently undergo chemotherapy to remove residual tumor after surgery, and many of these cytotoxic therapies are known to affect rapidly dividing cells such as ovarian follicles (Vassilakopoulou et al., 2016). The negative effects of chemotherapy on fertility have been demonstrated in patients with breast and colorectal cancer (Bines, et al., 1996; Avastin Prescribing Information). Additionally, infertility has been linked with decreased quality of life, primarily in women (O’Moore et al., 1983; Greil, 1997). Fertility treatments are available for women undergoing cancer treatment, however it is unknown whether these treatments are routinely discussed with glioma patients before initiating chemotherapy. OBJECTIVE: The primary goal of this study was to assess whether female glioma patients are being effectively counselled on their possible loss of fertility and their choices for fertility treatment prior to beginning chemotherapy. To this end, it was also important to understand the barriers preventing patients from obtaining information related to their fertility. Another principle goal of this study was to describe the effects of chemotherapy on a sample of women with glioma. Finally, this study sought to understand the priorities of women with glioma in regards to family planning, and to address these priorities in the context of a comprehensive fertility preservation discussion. METHODS: To assess these endpoints, a survey was designed and delivered to patients being treated at the Neuro-oncology clinic of the University of California, San Francisco. Eligible candidates were identified prior to a clinic visit, and patients were asked whether they would like to participate in the survey. Consenting patients then completed the survey at home or in the clinic. Seventy two women completed the survey. Data was analyzed using STATA Software Version 10.0. RESULTS: Analysis of the survey results showed that only 35% of women receiving chemotherapy reported having a discussion regarding fertility preservation prior to beginning treatment. Of those who reported having this discussion, only 80% were aware that chemotherapy could negatively affect their fertility. Many women reported that while fertility preservation was not important to them at the time of diagnosis, it was a priority for them at the time of survey completion. Most women surveyed expressed a desire to have a fertility preservation discussion with a reproductive specialist. CONCLUSIONS: The data obtained in this study suggest a lack of understanding of the negative effects of chemotherapy which may be addressed with a more comprehensive fertility discussion with glioma patients prior to beginning treatment. Although interest in having children tends to decrease after cancer treatment, the majority of respondents still report wanting a child after treatment. The priorities of women in the study reflect a concern for the health of their future offspring which may be best addressed prior to beginning treatment in order to increase their chances of conceiving at a later date.

Neuroinflammation is an important contributor to the pathogenesis of many neurological diseases. A key component of the innate immune response in the central nervous system is the migration of neutrophils into the brain parenchyma, where they exacerbate neuronal injury and worsen clinical outcome. A greater understanding of the mechanisms underlying neutrophil influx into the brain may aid the development of novel therapeutic interventions for the variety of diseases to which neutrophils contribute, notably including stroke and epilepsy. In vitro evidence implicates the pro- inflammatory cytokine, interleukin-1α (IL-1α), derived from platelets as a key mediator of cerebrovascular inflammation and neutrophil migration across brain endothelial cells.The aim of the work in this thesis was to test if this mechanism is important in vivo.We investigated the contribution of platelets and IL-1 in a murine model of neutrophil migration into the peritoneal cavity in response to injection of lipopolysaccharide (LPS). Depletion of platelets abrogated the migration of neutrophils in response to LPS- induced peritonitis, indicating an important role for platelets in the process. Genetic knockout of IL-1 had no effect on neutrophil influx, demonstrating that migration in the peritoneum occurs independently of IL-1.The discovery that neutrophil migration in LPS-induced peritonitis was independent of IL-1 contrasted with the finding that platelet-derived IL-1 was a mediator of neutrophil influx across mouse brain endothelial cells in vitro. The question arose as to whether IL-1 was required as a mediator of neutrophil migration in extra-cerebral tissues. Hence, we tested the contribution of platelets and IL-1 in two further in vivo models of neutrophil migration: LPS injection into a subcutaneous air pouch, and acute lung injury induced by LPS inhalation. Platelet depletion significantly reduced neutrophil migration into the air pouch in response to LPS, yet had no effect in acute lung injury. This indicated that neutrophil migration into the air pouch was dependent on platelets, and that migration into the lungs was platelet-independent. LPS induced the same degree of neutrophil migration in wild-type and IL-1 knockout mice, demonstrating that IL-1 was not required for neutrophil migration in either model.To determine the contribution of platelets and IL-1 to neutrophil migration in response to cerebrovascular inflammation, we injected LPS into the mouse striatum. In this model, neutrophil influx to the brain parenchyma in response to LPS was reduced by depletion of circulating platelets, and inhibition of the platelet adhesion molecule, GpIb. Genetic knockout of IL-1α significantly reduced the number of invading neutrophils induced by LPS. These data confirmed that both platelets and IL-1α were important contributors to cerebral neutrophil migration in vivo. To determine whether platelets in systemic circulation may be the source of IL-1α, we treated mice with IL-1 receptor antagonist or anti-IL-1 antibodies to block systemic IL-1 action. Neither intervention affected cerebral neutrophil migration in response to LPS, suggesting that the IL-1α that mediates neutrophil migration may originate in the brain.Overall, these data demonstrate that IL-1α and platelets make an important contribution to neutrophil migration to the brain, yet independently of each other. Our data also suggest there may be specific mechanisms driving innate immune responses in vivo even in response to the same inflammatory stimulus.

The Distal-less homeobox (Dlx) genes encode homeodomain transcription factors that play important roles in the development of limbs, sensory organs, branchial arches and the forebrain. In the forebrain, Dlx1 and Dlx2 are expressed in neuronal progenitor cells and play essential roles in GABAergic neuron differentiation and migration. In order to understand the fate of neuronal progenitor cells that express dlx1a/2a genes in the brain, we produced lines of Tg(dlx1a/2a:CreERT2) transgenic fish expressing the CreERT2 recombinase driven by regulatory elements from the dlx1a/2a locus. CreERT2 expression in these fish faithfully recapitulates that of dlx1a/2a genes in the forebrain. These fish were mated with Tg(ubi:Switch) reporter fish that express a loxP-flanked GFP gene followed by mCherry, driven by the ubiquitin promoter. Upon tamoxifen treatment, the double transgenic fish express mCherry in dlx1a/2a-expressing cells. Live imaging data showed that mCherry-expressing cells were observed first in the telencephalon and prethalamus, regions from which they migrated and populated the telencephalon, prethalamus and hypothalamus by 10dpf. Fate mapping of mCherry-expressing cells in double transgenic fish demonstrated that a majority of dlx1a/2a-expressing cells give rise to GABAergic neurons. Furthermore, as zebrafish produce new neurons throughout life, the role of dlx1a/2a during adult neurogenesis was examined. Our preliminary data showed that dlx1a/2a-expressing progenitor cells populate various domains of the forebrain during adult neurogenesis. Our lineage tracing system provides a powerful tool to investigate the origin of GABAergic neuron progenitors and the mechanisms by which they populate or repopulate the adult brain.